Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin.
OBJECTIVE
Current therapy for lung cancer involves multimodality therapies. However, many patients are either refractory to therapy or develop drug resistance. KRAS and epidermal growth factor receptor (EGFR) mutations represent some of the most common mutations in lung cancer, and many studies have shown the importance of these mutations in both carcinogenesis and chemoresistance. Genetically engineered murine models of mutant EGFR and KRAS have been developed that more accurately recapitulate human lung cancer. Recently, using cell-based experiments, we showed that platinum-based drugs and the antidiabetic drug rosiglitazone (PPARgamma ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARgamma/carboplatin combination in these more relevant models of drug resistant non-small cell lung cancer.


METHODS
Tumorigenesis was induced by activation of either mutant KRAS or EGFR. Mice then received either rosiglitazone or carboplatin monotherapy, or a combination of both drugs. Change in tumor burden, pathology, and evidence of apoptosis and cell growth were assessed.


RESULTS
Tumor burden remained unchanged or increased in the mice after monotherapy with either rosiglitazone or carboplatin. In striking contrast, we observed significant tumor shrinkage in mice treated with these drugs in combination. Immunohistochemical analyses showed that this synergy was mediated via both increased apoptosis and decreased proliferation. Importantly, this synergy between carboplatin and rosiglitazone did not increase systemic toxicity.


CONCLUSIONS
These data show that the PPARgamma ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.
Girnun
Geoffrey D
GD
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Chen
Liang
L
Silvaggi
Jessica
J
Drapkin
Ronny
R
Chirieac
Lucian R
LR
Padera
Robert F
RF
Upadhyay
Rabi
R
Vafai
Scott B
SB
Weissleder
Ralph
R
Mahmood
Umar
U
Naseri
Elnaz
E
Buckley
Stephanie
S
Li
Danan
D
Force
Jeremy
J
McNamara
Kate
K
Demetri
George
G
Spiegelman
Bruce M
BM
Wong
Kwok-Kin
KK
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000502:physiology; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000819:agonists; D047428:Protein Kinase Inhibitors / Q000009:adverse effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014598:Uteroglobin / Q000502:physiology
D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D014598:Uteroglobin; D016190:Carboplatin; D066246:ErbB Receptors